Document Detail


Effects of transcription factor activator protein-1 on interleukin-8 expression and enteritis in response to Clostridium difficile toxin A.
MedLine Citation:
PMID:  17639289     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Clostridium difficile toxin A causes acute colitis associated with intense infiltration of neutrophils. Although C. difficile toxin A is known to induce nuclear factor-kappaB-mediated chemokine expression in intestinal epithelial cells, little is known about its effect on the regulation of activator protein-1 (AP-1) by mitogen-activated protein kinase (MAPK). In the present study, we investigated whether the MAPK and AP-1 signaling pathway is involved in interleukin (IL)-8 expression and enteric inflammation in response to stimulation with toxin A. Toxin A activated MAPK and AP-1 composed of c-Jun/c-Fos heterodimers in primary intestinal epithelial cells and HT-29 cell lines. Transfection with mutant genes for Ras, c-Jun, p38, or c-Jun N-terminal kinase (JNK) significantly inhibited C. difficile toxin A-induced activation of AP-1 and expression of IL-8 in HT-29 cell lines. Furthermore, the p38 inhibitor SB203580 attenuated toxin A-induced inflammation in vivo in the mouse ileum, evidenced by a significant decrease in neutrophil infiltration, villous destruction, and mucosal congestion. Our results suggest that the Ras/MAPK cascade acts as the upstream signaling for AP-1 activation and IL-8 expression in toxin A-stimulated intestinal epithelial cells and may be involved in the development of enteritis after infection with toxin A-producing C. difficile.
Authors:
Jin Young Lee; Hye Ri Park; Yu-Kyoung Oh; Yeong-Jeon Kim; Jeehee Youn; Joong-Soo Han; Jung Mogg Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-07-18
Journal Detail:
Title:  Journal of molecular medicine (Berlin, Germany)     Volume:  85     ISSN:  0946-2716     ISO Abbreviation:  J. Mol. Med.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-10     Completed Date:  2008-03-13     Revised Date:  2011-07-08    
Medline Journal Info:
Nlm Unique ID:  9504370     Medline TA:  J Mol Med (Berl)     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1393-404     Citation Subset:  IM    
Affiliation:
Department of Microbiology and Institute of Biomedical Science, Hanyang University College of Medicine, Seoul, 133-791, South Korea.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bacterial Toxins / toxicity*
Colon / drug effects*,  enzymology,  metabolism,  pathology
Dimerization
Disease Models, Animal
Enterotoxins / toxicity*
Enzyme Activation
Epithelial Cells / drug effects*,  enzymology,  metabolism,  pathology
Genes, ras
HT29 Cells
Humans
Ileitis / chemically induced,  enzymology,  metabolism*,  pathology,  prevention & control
Imidazoles / pharmacology,  therapeutic use
Interleukin-8 / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Signaling System / drug effects*
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Mitogen-Activated Protein Kinases / antagonists & inhibitors,  genetics,  metabolism*
Mutation
Protein Kinase Inhibitors / pharmacology,  therapeutic use
Proto-Oncogene Proteins c-fos / metabolism
Proto-Oncogene Proteins c-jun / metabolism
Pyridines / pharmacology,  therapeutic use
Time Factors
Transcription Factor AP-1 / metabolism*
Transfection
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/Bacterial Toxins; 0/Enterotoxins; 0/Imidazoles; 0/Interleukin-8; 0/Protein Kinase Inhibitors; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/Pyridines; 0/SB 203580; 0/Transcription Factor AP-1; 0/tcdA protein, Clostridium difficile; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

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